Functional connectivity is defined as a correlation in neural activity between distinct
regions of the brain. Several recent studies have demonstrated areas of low-frequency
functional connectivity inherent to brain tissue at rest. These oscillations can be measured
using functional magnetic resonance imaging (fMRI) and appear to be synchronized between
related areas of the brain.
To date, no investigators have examined the effects of low-dose anesthesia on functional
connectivity. This study will image the human brain under conditions of rest, and low-dose
anesthetic induced sedation. Quality of the acquired signals will be evaluated and
functional networks in the brain will be examined. Of interest is whether administration of
a low-dose anesthetic disrupts functional connectivity in the brain, and whether a
disruption of functional connectivity is responsible for the reported analgesic and
antidepressant effects of a anesthetic.
Participation in the study includes four visits: an in-person interview, an initial fMRI
scan, the anesthesia infusion, and a second fMRI scan. There is an optional follow-up fMRI
scan one week post infusion.
A phencyclidine derivative developed by Parke-Davis represented an attempt to mimic
phencyclidine anesthesia without inducing the severe psychomimetic reactions of its parent
compound. Initial reports were promising and received great enthusiasm. At high doses, the
drug was found to provide profound analgesia whilst preserving airway reflexes. It induced
reliable amnesia, yet could be delivered as a simple injection. It was claimed at the time
that this anesthetic heralded a new phase in the history of anesthesia. Today, over 40 years
since the anesthetic was introduced at Michigan, there has been a resurgence of interest in
this old drug. A growing number of investigators are studying the effects of anesthesia on
human subjects. There is currently tremendous interest in anesthesia as an opioid sparing
agent, a model for schizophrenia, an antidepressant, and as an N-Methyl D-Aspartate (NMDA)
antagonist in complex regional pain syndromes.
Functional connectivity is a measure of low-frequency oscillations (<0.08 Hz) that are
inherent to brain tissue at rest. These oscillations are measured on fMRI, and appear to be
synchronized between related areas of the brain. Although research in this area is still in
its infancy, studies of the motor, auditory, visual, and sensorimotor systems, have shown
that functionally related areas of the brain produce correlated low-frequency oscillations.
This fascinating finding raises the possibility of a new approach to studying brain function
as well as a potential tool for the diagnosis of disease. Recent fMRI studies of the
precentral gyrus have demonstrated the ability of functional connectivity studies to
differentiate healthy volunteers from patients with multiple sclerosis. Additional research
is ongoing to determine whether functional connectivity will prove useful in the diagnosis
of early Alzheimer's disease.
Recent research in functional connectivity has identified regions in the brain active at
rest. These regions are often referred to at the "Default-mode network" (DMN). Activity in
the DMN is increased in the brain at rest and decreased when a subject concentrates on a
mental task. The first fMRI study examining functional connectivity in chronic pain patients
was published in a recent issue of the Journal of Neuroscience. In this study abnormal
patterns of functional connectivity were seen in chronic pain patients. Specifically, a
dysfunction in down-regulating the DMN was seen. The chronic pain patients did not
deactivate the medial prefrontal cortex, amygdala, or posterior cingulate cortex to the same
degree as healthy controls.
The only fMRI study examining functional connectivity in major depression was published in
September of 2007. This study also noted a dysfunction in the DMN. Depressed subjects were
found to have increased network functional connectivity in the subgenual cingulate cortex,
thalamus, orbitofrontal cortex, and the precuneus. Notably, the subgenual cingulate cortex
is the location of a recent clinical trial suggesting that deep brain stimulation to this
region may ameliorate symptoms of patients with severe refractory depression.
Interest in anesthesia for the treatment of chronic pain and depression has grown in recent
years. Although there have been no randomized trials of low-dose anesthesia in chronic pain
patients, the evidence currently available indicates it is most effective in the treatment
of allodynia, hyperalgesia, and hyperpathia. For depression, there has been one randomized,
placebo-controlled, double blinded crossover study. In the depression trial, robust and
rapid antidepressant effects were found to result from a single intravenous dose of
anesthesia and last for at least a week.
To examine functional connectivity in the human brain both at rest and after anesthetic
sedation using functional magnetic resonance imaging (fMRI).
1. Measure the degree of functional connectivity in three study groups (healthy
volunteers, chronic back pain, and refractory depression).
2. Analyze for differences in baseline functional connectivity.
3. Measure changes in functional connectivity after IV low-dose anesthetic sedation.
4. Document study group differences in anesthetic response.
5. Measure for any correlation between fMRI changes and therapeutic effects.
Participation in this study includes four main visits and an optional follow-up visit. The
first visit is a baseline interview session to assess participant eligibility using a
structured interview. The second visit is an initial fMRI scan at the fMRI center. The third
visit is the anesthetic infusion at the hospital; management of any adverse events during
the infusion will be monitored by the Post Anesthesia Care Unit ( PACU) personnel. The
fourth visit is a follow-up fMRI scan at the fMRI center. There is an optional one week
follow-up visit at the fMRI center for a final fMRI scan.
fMRI Statistical Analysis: The imaging experiments and analysis of subject-specific data
will lead to maps corresponding to separate measures: resting state functional connectivity
maps, and measures of cerebral blood flow (CBF). Final inferences will be made at the voxel
level and for anatomically specific regions-of-interest (ROIs). The voxel-based analysis
will be performed through the generation of summary images referred to as statistical
parametric maps (SPMs) representing before-infusion vs. after-infusion, and, as data in the
two patient groups become available, two-way ANOVA results of ketamine infusion state and
patient diagnosis (chronic pain or refractory depression). The ROI-based analysis will be
driven by the a priori selected fronto-limbic regions of interest generated in the
self-reflection task, and by the anatomical nodes in the default mode network given in the
(4) Ability to tolerate small, enclosed spaces without anxiety; (6) English fluency.
- Pregnant or trying to become pregnant.
- history of serious head injury;
- possibility of ferrous metals within the body, e. g. aneurysm clips, retained
particles; or metal that would impair the magnetic resonance (MR) signal, e.g., some
- Smoking usage > 10 cigarettes per day
- Daily intake of caffeine exceeds 2 cups of coffee per day
- Unstable cardiac problems (e.g. severe or poorly treated hypertension, unstable
arrhythmia, etc.) or concurrent medications for which anesthesia would be
- Patients with a current general medical illness that is life threatening or
inadequately treated will be excluded: moderate-to-severe chronic pain, evidence of
fracture or malignancy, inflammatory joint disease, severe physical impairment (e.g.,
bilateral amputation, blindness), morbid obesity, autoimmune/inflammatory diseases,
cardiopulmonary disorders (i.e., angina, congestive heart failure, COPD), chronic
renal insufficiency, uncontrolled endocrine or allergic disorders (i.e.,
hyper-/hypothyroidism, diabetes, allergic rhinitis), malignancy.
- Taking any medication, prescription or non-prescription, with psychotropic effects.
- History of psychiatric or neurological illness; History of substance abuse or
dependence Positive urine toxicology screen.
Refractory Depression Group:
- Meets all above control group screening criteria except history of psychiatric
illness and prescription medication usage
- Included subjects will have a Diagnostic and Statistical Manual of Mental Disorders
IV (DSM-IV) diagnosis of major depressive disorder, recurrent or chronic,
moderate-to-severe, without psychotic features, with medication resistance, accepted
with agreement by two different psychiatrists. For this study, treatment resistance
is defined as ≥2 failed adequate antidepressant trials.
- Patients with a DSM-IV diagnosis of bipolar disorder, schizophrenia, or
schizoaffective disorder will be excluded. Any history of antidepressant- or
substance- induced hypomania or mania will be excluded.
- Subjects will be free of comorbid substance abuse or dependence for at least 3
months, with a negative urine toxicology screen.
- No current suicide plan or intent.
- Comorbid Axis I anxiety disorder diagnoses will be permitted if they do not require